Learning and memory, nerve development, Alzheimer's disease, epilepsy, seizures and other electroconvulsive disorders, pain, fibromyalgia, schizophrenia and psychosis, depression and other affective disorders, autism, Parkinson's disease, attention deficit disorder, attention deficit hyperactivity disorder, anesthesia, and neurodegeneration have all been linked to the activity and regulation of the N-methyl-D-aspartate receptor (NMDAR; 1,2). The NMDAR, a non-selective ion channel present on many types of nerve cells, regulates and modifies nerve growth and is directly linked to signaling and nerve activity in the brain. The development of NMDAR modulators, including NMDAR antagonists and partial NMDAR antagonists, as new diagnostic agents and new therapeutic drugs, is a promising area of research.
A number of bridged diindoles that are structurally distinct from compounds known to modify NMDAR activity, as well as from known therapeutic drugs, have been identified as potential NMDAR ligands, partial NMDAR antagonists, NMDAR antagonists, and modulators of NMDAR activity. Computer-based (in silico) modeling studies that assess the affinity and specificity of the chemical interactions between small molecules and large biological molecules, such as the NMDAR, reveal that these novel compounds interact with NMDAR at specific receptor binding sites in unique ways not previously reported in the literature. Studies reveal that these compounds likely act as NMDAR antagonists or partial NMDAR antagonists. This includes activity as antagonists at one or more NMDAR NR2 isoform receptor sites, including NMDAR NR2A and NR2B.
Preliminary in silico modeling data indicate the existence of multiple NMDAR binding sites for these compounds, suggesting that they could be useful for regulating multiple nervous system and brain functions and diseases. In silico modeling experiments using computer programs such as Discovery Studio and AutoDock 4 for modeling interactions of the compounds with crystal structure models of the NMDAR reveal that these compounds bind specifically and with high affinity to sites on the NMDAR including subunit NR2 isoforms, such as NMDAR NR2A and NR2B, at sites that include the entrance to a cavity that also contains the activating agonist (glutamate) binding site.
Bridged diindole and bis-diindole compounds and their derivatives, both synthetic and naturally occurring, have been reported. Most of these have physical-chemical properties and commercial utility completely unrelated to biological or pharmacological activity, as evidenced by their use as combustion modifiers, polymerization initiators and promoters, electrical conductors, and glass materials (3,4). A number of bridged diindole compounds, including those with a methylene, a ketone, a sulfide, and a sulfone as bridging moieties, do have biological activity. However, their chemical structures are clearly distinct from those contemplated in the present invention, as are their purported biological activities, which are completely distinct from the NMDAR antagonist activity and nervous system effects contemplated by the compounds revealed in the present invention. These include: DNA-binding and alkylating agents proposed for cancer treatment (5,6); antibiotics and antibacterial agents (7-9); and biological effects related to the serotonin (5-HT) receptor (10,11).
A number of drugs that modulate NMDAR activity, including NMDAR antagonists, are available or are under development for treating these aforementioned NMDAR-related nervous system pathologies (12). These include: Alzheimer's disease and other memory disorders (13); status epilepticus and other electroconvulsive disorders (14); pain-related disorders (15,16); schizophrenia (17); autism (18); and depression and other mood disorders (19-21), including the effects of NMDAR activity modulation on depression and mood disorders by molecular modeling methods (22).
Given the enormous therapeutic potential of NMDAR antagonists as palliatives and treatments for nervous system disorders, several published patents and patent applications teach the synthesis and use of novel NMDAR modulators, including NMDAR antagonists, as therapeutic agents for nervous system disorders. Although completely unrelated chemically to the compounds that are the subject matter of the present invention, these patents and applications describe specific NMDAR antagonists, discrete NMDAR subunit antagonists, and the proposed therapeutic activity of NMDAR ligands for nervous system pathologies (23-27).
However, many of these agents have a number of shortcomings. For instance, the agents may be poorly soluble in aqueous and biological fluids or may be extremely hygroscopic, thereby complicating their formulation and delivery to patients and to their active sites. Moreover, the agents may be chemically and/or physically unstable. They may be inherently toxic, or they may undergo conversion to toxic degradants in storage or when metabolized. Many of these agents are not absorbed by the oral route, thus requiring more expensive and invasive modes of administration, such as needle injection. Of even greater importance is that patients may become refractory to these drugs over time. Many patients require multi-drug therapy in order to achieve a desired clinical effect. In addition, many current NMDAR-modulating agents cause unwanted side effects, neurotoxicities, and drug interactions.
As an example, the drug treatments currently available for one subset of the aforementioned, NMDA-influenced nervous system pathologies, epilepsy and other electroconvulsive disorders, exemplify many of these therapeutic drug limitations. These include refractory loss of drug effect, the need for multiple drug therapy, undesirable side effects, drug and dietary interactions, and a decrease in patient quality of life (28). As novel NMDAR-modulating compounds, such as those that are included in the subject matter of the present invention, are identified and developed, the clinician will have expanded pharmaceutical options when designing an effective treatment protocol for each patient. This possibility clearly underscores the utility of the present invention.
The need for novel compounds that interact with the NMDAR as therapeutic agents is further underscored by the fact that many NMDA-modulating compounds, such as anti-epilepsy compounds, are effective in the treatment of other central nervous system disorders, including bipolar disorder, fibromyalgia, migraine prophylaxis, neuropathic pain, and chronic pain, alone or in combination with other biologically active agents. These novel compounds would ideally interact chemically with the NMDAR in a manner that is distinct from current NMDAR-modulating agents and ligands. They might also interact with one or more sites in the central nervous system that are distinct from the purported sites and modes of action of current agents.